EP0358995A2 - Use of transglutaminases as immunosuppressive agents - Google Patents

Use of transglutaminases as immunosuppressive agents Download PDF

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Publication number
EP0358995A2
EP0358995A2 EP89115614A EP89115614A EP0358995A2 EP 0358995 A2 EP0358995 A2 EP 0358995A2 EP 89115614 A EP89115614 A EP 89115614A EP 89115614 A EP89115614 A EP 89115614A EP 0358995 A2 EP0358995 A2 EP 0358995A2
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transglutaminase
therapy
medicament
produced
plasminogen activator
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EP0358995B1 (en
EP0358995A3 (en
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Thomas Dr. Stief
Norbert Prof. Dr. Heimburger
Hans Ulrich Dr. Schorlemmer
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CLS BEHRING GmbH
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Behringwerke AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1025—Acyltransferases (2.3)
    • C12N9/104—Aminoacyltransferases (2.3.2)
    • C12N9/1044—Protein-glutamine gamma-glutamyltransferase (2.3.2.13), i.e. transglutaminase or factor XIII

Definitions

  • the invention relates to the use of a transglutaminase in a method for producing an immunosuppressant.
  • Macrophages and polymorphonuclear neutrophil leukocytes play a major role in the immune response of the organism. They have an attack system that consists of proteases and potent oxidants (N-chloramines and oxygen radicals). These proteases and oxidants influence and strengthen the immune response.
  • Immune response is to be understood as the reaction of immune-competent cells such as the monocyte / macrophage system to inflammation, infection, tissue remodeling and tissue repair stimuli.
  • the monocyte / macrophage system has a variety of tasks in the entire organism, since blood monocytes migrate into a wide variety of tissues, not least to perform specific immunological tasks here.
  • the monocytes differentiate into alveolar macrophages in the lungs, from copper's stellate cells in the liver, to osteoclasts in the bones, to microglial cells in the central nervous system (CNS), to mesangial macrophages in the kidney, to synovial covering cells in the synovial mucosa and in the body cavities to pleura - or peritoneal macrophages.
  • Inhibitors of these macrophages and PMN are of great clinical interest since a variety of human diseases are associated with increased macrophage activity.
  • Such conditions can be an abnormal reaction of the immune system (hyperergic state) or a reaction of the immune system against the body's own tissue.
  • F XIII has an immunosuppressive effect in vivo on transplant models.
  • the invention therefore relates to the use of a transglutaminase, preferably factor XIII, for the production of an immunosuppressant.
  • an immunosuppressant in which such an immunosuppressant can be used are, for example, those with chronic inflammatory events such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barre Syndrome, psoriasis and other autoimmune diseases, degenerative diseases such as Parkinson's disease, arteriosclerosis, neoplastic diseases, hyperergic-allergic diseases, graft versus host reactions, shock syndrome such as ARDS (Adult Respiratory Distress Syndrome), burns disease, consumption coagulopathy and sepsis.
  • ARDS Adult Respiratory Distress Syndrome
  • Such an agent can also be of importance for infectious diseases such as AIDS.
  • F XIII prevents the formation of superoxide ions.
  • Transglutaminases also work allergic encephalomyelitis (AE), which is considered a model disease of the human disease multiple sclerosis.
  • Neoplastic diseases can also be caused by a pathologically increased activity of leukocytes. These include e.g. B. histocytosis X, leukaemias, preferably of the myeloid series, and certain tumors that behave like macrophages or tumors that rely on macrophage support (for example, to treat the tumor stroma in the sense of angiogenesis). In these neoplastic diseases, the immunosuppressive therapy according to the invention is therefore also recommended.
  • Reactions of the immune system that go beyond the norm and the associated pathologically increased release of oxygen radicals and / or plasminogen activators can also be found in reperfusion states, ie. H. Sudden blood flow through a previously underperfused tissue, with high-proof oxygen ventilation, in clinical use or poisoning with e.g. B. paraquat, treatment with cis-platinum, adriamycin, nitrofurantoin, bleomycin, streptozotocin and other diabetogenic substances, radiation therapy and associated tissue damage.
  • Known measures that are suitable for suppressing the immune system include treatment with antibodies against lymphoid tissue, ionizing radiation and chemical substances.
  • Such aggressive treatment is accompanied by pronounced side effects: organotoxicity, sterility with cytostatics and ionizing radiation, brain edema with tranexamic acid, anti-antibody formation with the risk of Rays and chemical substances.
  • Such aggressive treatment is accompanied by pronounced side effects: organotoxicity, sterility in the case of cytostatics and ionizing radiation, brain edema in the case of tranexamic acid, anti-antibody formation with the risk of serum sickness when treated with antibodies.
  • transglutaminases to inhibit damage to tissue at risk during reperfusion, inflammatory events, subarachnoid hemorrhage, autoimmune diseases, degenerative diseases, arteriosclerosis, neoplastic diseases (such as leukemia, histiocytosis X and others), hyperergic allergic diseases, intolerance to burns, transplant intolerance, transplant disease premature detachment and pre-eclampsia, shock syndrome depends on a number of factors, such as the age and weight of the patient and the clinical condition.
  • transglutaminase preferably F XIII
  • F XIII transglutaminase
  • Transglutaminases such as F XIII can be stabilized by adding stabilizers such as albumin, polygelin or an amino acid such as glycine ( * 1 E corresponds to the amount of F XIII in 1 ml of human citrated plasma).
  • Transglutaminases such as F XIII can also be administered topically enough for local therapy and prophylaxis of wound healing disorders, graft rejection, asthmoid bronchial diseases, burns and other diseases associated with increased macrophage activity.
  • transglutaminases and a fibrinolytic such as tissue plasminogen activator (t-PA), urokinase, streptokinase or plasminogen streptokinase activator complex for lysis therapy are medically indicated, preferably for arterial occlusions such as myocardial infarction or apoplex.
  • tissue plasminogen activator t-PA
  • urokinase urokinase
  • streptokinase streptokinase
  • plasminogen streptokinase activator complex for lysis therapy are medically indicated, preferably for arterial occlusions such as myocardial infarction or apoplex.
  • a combined use of transglutaminases and fibrinolytic enables the immediate inhibition of tissue damage (e.g. necrosis) during and after acute reperfusion due to hyperactive white blood cells.
  • PAI-2 plasminogen activator inhibitor of placental origin
  • an effective dose of PAI-2 is generally from 30 to 30,000 urokinase-inhibiting units / kg / 24 hours, i.e. 52.5 - 225,000 units for a 75 kg patient for systemic application.
  • Polymorphonuclear granulocytes and mononuclear phagocytes were obtained from peripheral blood of healthy donors and tested for various functions after administration of the preparation.
  • the chemiluminescence reaction and the secretion of lysosomal enzymes were investigated as parameters of the phagocyte function. Both the effect of factor XIII on the non-activated (-IC) and on the phagocytes (+ IC) activated by immune complexes was measured.
  • mice Female NMRI mice (18-20 g) were administered factor XIII in concentrations of 0.25-2.5 U / animal parenterally.
  • the controls received equal volumes (0.5 ml) of the solvent (physiologically buffered saline, pH 7.2). Two hours and 24 hours later, the mice were sacrificed, the macrophages were taken from the abdominal cavity, and an activity was determined using chemiluminescence, as described in Example 1.
  • factor XIII lowers the activity of macrophages taken from mice previously treated with the preparation. The suppression was observed in chemiluminescence both after 2 hours and after 24 hours after application of the substance with and without the addition of immune complexes in vitro.
  • Factor XIII (units / ml) Enzyme release (N-Ac-Glu, mU / ml) - IC + IC 0 8365 ⁇ 219 16205 ⁇ 1703 2.5 2514 ⁇ 574 2723 ⁇ 333 0.6 4254 ⁇ 541 6428 ⁇ 1112 0.3 6358 ⁇ 632 10320 ⁇ 1030 0.03 7703 ⁇ 288 13483 ⁇ 794 Influence of factor XIII on macrophage activity (1 x 106 cells) in vivo.

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Abstract

It is described how transglutaminases can be used in a process for preparing an immunosuppressive agent. Also described is a medicament containing a transglutaminase and a plasminogen activator inhibitor.

Description

Die Erfindung betrifft die Verwendung einer Transglutami­nase in einem Verfahren zur Herstellung eines Immunsup­pressivums.The invention relates to the use of a transglutaminase in a method for producing an immunosuppressant.

Makrophagen und polymorphkernige neutrophile Leukozyten (PMN) sind an der Immunantwort des Organismus in wesent­licher Weise beteiligt. Sie verfügen über ein Angriffs­system, das zum einen aus Proteasen und zum anderen aus potenten Oxidantien (N-Chloramine und Sauerstoffradikale) besteht. Über diese Proteasen und Oxidantien beeinflussen und verstärken sie die Immunantwort.Macrophages and polymorphonuclear neutrophil leukocytes (PMN) play a major role in the immune response of the organism. They have an attack system that consists of proteases and potent oxidants (N-chloramines and oxygen radicals). These proteases and oxidants influence and strengthen the immune response.

Unter Immunantwort soll verstanden werden die Reaktion immunkompetenter Zellen wie Monozyten/Makrophagen-­System auf Entzündungs-, Infektions-, Gewebeumbau- und Gewebereparatur-Reize. Dem Monozyten/Makrophagen-System kommen vielfältige Aufgaben im gesamten Organismus zu, da Blutmonozyten in verschiedenste Gewebe einwandern, um hier nicht zuletzt spezifische immunologische Aufgaben zu übernehmen. So differenzieren sich die Monozyten in der Lunge zu Alveolarmakrophagen, in der Leber zu von Kupfferschen Sternzellen, im Knochen zu Osteoklasten, im zentralen Nervensystem (ZNS) zu Mikrogliazellen, in der Niere zu Mesangialmakrophagen, in der Gelenkschleimhaut zu Synovialisdeckzellen und in den Körperhöhlen zu Pleura- bzw. Peritonealmakrophagen.Immune response is to be understood as the reaction of immune-competent cells such as the monocyte / macrophage system to inflammation, infection, tissue remodeling and tissue repair stimuli. The monocyte / macrophage system has a variety of tasks in the entire organism, since blood monocytes migrate into a wide variety of tissues, not least to perform specific immunological tasks here. The monocytes differentiate into alveolar macrophages in the lungs, from copper's stellate cells in the liver, to osteoclasts in the bones, to microglial cells in the central nervous system (CNS), to mesangial macrophages in the kidney, to synovial covering cells in the synovial mucosa and in the body cavities to pleura - or peritoneal macrophages.

Inhibitoren dieser Makrophagen und PMN sind von hohem klinischen Interesse, da eine Vielzahl menschlicher Erkrankungen mit erhöhter Makrophagenaktivität einhergeht.Inhibitors of these macrophages and PMN are of great clinical interest since a variety of human diseases are associated with increased macrophage activity.

Es kann Zustände geben, in denen die funktionelle Unterdrückung eines oder mehrerer Kompartimente des Immunsystems wünschenswert ist. Solche Zustände können eine über das Normalmaß hinausschießende Reaktion des Immunsystems (hypererger Zustand) oder eine Reaktion des Immunsystems gegen körpereigenes Gewebe sein.There may be conditions in which functional suppression of one or more compartments of the immune system is desirable. Such conditions can be an abnormal reaction of the immune system (hyperergic state) or a reaction of the immune system against the body's own tissue.

Substanzen, die in der Lage sind, die biologische Wirkung von Makrophagen zu inhibieren, können immunsuppressiv wirken. Es besteht großer Bedarf nach a) nebenwirkungs­armen und b) hochspezifischen Immunsuppressoren. Die in der Klinik vielfach verwandten Kortikoidabkömmlinge erfüllen weder a) noch b).Substances that are able to inhibit the biological effects of macrophages can have an immunosuppressive effect. There is a great need for a) low-side effects and b) highly specific immunosuppressors. The corticoid offspring, which are widely used in the clinic, do neither a) nor b).

Als in in vitro-Testsystemen mit Makrophagen Substanzen auf Sauerstoffradikal-Sekretion inhibierende Wirkung getestet wurden, wurde überraschenderweise gefunden, daß Inhibitoren der Ornithyldecarboxylase besonders vom Typ der Transglutaminasen, vorzugsweise F XIII, sowohl plazentaren als auch plasmatischen Ursprungs, in physiologischen Konzentrationen stark inhibierend auf die auf Sauerstoffradikal-Freisetzung beruhende Chemilumi­neszenzreaktion von Makrophagen wirkt.When in vitro test systems with macrophages substances were tested to inhibit oxygen radical secretion, it was surprisingly found that inhibitors of ornithyl decarboxylase, particularly of the transglutaminase type, preferably F XIII, of both placental and plasmatic origin, strongly inhibiting the physiological concentrations in physiological concentrations chemiluminescent reaction of macrophages based on oxygen radical release acts.

Es wurde weiterhin überraschenderweise gefunden, daß F XIII in vivo an Transplantationsmodellen immunsuppressiv wirkt.It was also surprisingly found that F XIII has an immunosuppressive effect in vivo on transplant models.

Gegenstand der Erfindung ist daher die Verwendung einer Transglutaminase, vorzugsweise von Faktor XIII, zur Herstellung eines Immunsuppressivums.The invention therefore relates to the use of a transglutaminase, preferably factor XIII, for the production of an immunosuppressant.

Krankheitsbilder, bei denen ein solches Immunsuppressivum angewendet werden kann, sind beispielsweise solche mit chronisch entzündlichem Geschehen wie rheumatoider Arthritis, Morbus Crohn, Colitis ulcerosa, Multiple Sklerose, Guillain-Barre

Figure imgb0001
-Syndrom, Psoriasis und anderen Autoimmunerkrankungen, degenerativen Erkrankungen wie Morbus Parkinson, Arteriosklerose, neoplastischen Erkran­kungen, hyperergisch-allergischen Erkrankungen, Graft versus Host-Reaktionen, Schocksyndrom wie ARDS (Adult Respiratory Distress Syndrome), Verbrennungskrankheit, Verbrauchskoagulopathie und Sepsis. Auch bei infektiösen Erkrankungen wie AIDS kann einem solchen Mittel Bedeutung zukommen.Diseases in which such an immunosuppressant can be used are, for example, those with chronic inflammatory events such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barre
Figure imgb0001
Syndrome, psoriasis and other autoimmune diseases, degenerative diseases such as Parkinson's disease, arteriosclerosis, neoplastic diseases, hyperergic-allergic diseases, graft versus host reactions, shock syndrome such as ARDS (Adult Respiratory Distress Syndrome), burns disease, consumption coagulopathy and sepsis. Such an agent can also be of importance for infectious diseases such as AIDS.

Auch nach der Transplantation von körperfremdem Gewebe kommt es zu einer immunologischen Reaktion gegen das als fremd erkannte transplantierte Organ oder gegen den Empfängerorganismus im Sinne einer graft versus host-­Reaktion, was zu einer Abstoßung führt. Derartige Ab­stoßungskrisen können sich auch mit plazentarem Gewebe ergeben, welches vom mütterlichem Organismus z. T. auch als fremd erkannt wird und zu Plazentatrophoblaststö­rungen und vorzeitiger Plazentalösung führen kann. Es ist daher notwendig, das Immunsystem des Organempfängers oder des Transplantats zu unterdrücken, um das Überleben des Transplantats bzw. des Empfängers zu gewährleisten.Even after the transplantation of foreign body tissue, there is an immunological reaction against the transplanted organ recognized as foreign or against the recipient organism in the sense of a graft versus host reaction, which leads to rejection. Such rejection crises can also arise with placental tissue, which the maternal organism z. T. is also recognized as foreign and can lead to placental atrophoblast disorders and premature placental detachment. It is therefore necessary to suppress the immune system of the organ recipient or the graft in order to ensure the survival of the graft or the recipient.

Im Gegensatz zu der in der Klinik eingesetzten Superoxid-­dismutase, welche entstandene Superoxid-Ionen zu neutra­lisieren vermag, verhindert F XIII die Entstehung von Superoxid-Ionen. Transglutaminasen wirken auch bei allergischer Encephalomyelitis (AE), die als Modeller­krankung der menschlichen Krankheit Multiple Sklerose gilt.In contrast to the superoxide dismutase used in the clinic, which is able to neutralize superoxide ions, F XIII prevents the formation of superoxide ions. Transglutaminases also work allergic encephalomyelitis (AE), which is considered a model disease of the human disease multiple sclerosis.

Auch neoplastische Erkrankungen können mitbedingt sein durch eine pathologisch gesteigerte Aktivität von Leuko­zyten. Hierzu zählen z. B. Histocytosis X, Leukämien, vorzugsweise der myeloischen Reihe und bestimmte, sich wie Makrophagen verhaltende Tumoren oder Tumoren, die auf Unterstützung von Makrophagen angewiesen sind (z. B. zur Versorgung des Tumorstroma im Sinne von Angiogenese). Bei diesen neoplastischen Erkrankungen empfiehlt sich daher ebenfalls die erfindungsgemäße immunsupprimierende Therapie.Neoplastic diseases can also be caused by a pathologically increased activity of leukocytes. These include e.g. B. histocytosis X, leukaemias, preferably of the myeloid series, and certain tumors that behave like macrophages or tumors that rely on macrophage support (for example, to treat the tumor stroma in the sense of angiogenesis). In these neoplastic diseases, the immunosuppressive therapy according to the invention is therefore also recommended.

Über die Norm hinausschießende Reaktionen des Immun­systems und damit einhergehende pathologisch erhöhte Sauerstoffradikal- und/oder Plasminogenaktivator-Frei­setzung findet sich auch bei Reperfusionszuständen, d. h. plötzliche Blutdurchströmung eines zuvor minderperfun­dierten Gewebes, bei hochprozentiger Sauerstoffbeatmung, bei klinischem Einsatz bzw. Vergiftung mit z. B. Para­quat, Behandlung mit Cis-Platin, Adriamycin, Nitrofu­rantoin, Bleomycin, Streptozotocin und anderen diabeto­genen Substanzen, Bestrahlungstherapie und damit einher­gehenden Gewebeschäden.Reactions of the immune system that go beyond the norm and the associated pathologically increased release of oxygen radicals and / or plasminogen activators can also be found in reperfusion states, ie. H. Sudden blood flow through a previously underperfused tissue, with high-proof oxygen ventilation, in clinical use or poisoning with e.g. B. paraquat, treatment with cis-platinum, adriamycin, nitrofurantoin, bleomycin, streptozotocin and other diabetogenic substances, radiation therapy and associated tissue damage.

Zu den bekannten Maßnahmen, die für die Unterdrückung des Immunsystems geeignet sind, gehören die Behandlung mit Antikörpern gegen lymphatisches Gewebe, ionisierenden Strahlen und chemischen Substanzen. Eine derartige aggressive Behandlung geht einher mit ausgeprägten Nebenwirkungen: Organotoxizität, Sterilität bei Cytosta­tika und ionisierenden Strahlen, Hirnödem bei Tranexam­säure, Anti-Antikörperbildung mit Gefahr einer Strahlen und chemischen Substanzen. Eine derartige aggressive Behandlung geht einher mit ausgeprägten Nebenwirkungen: Organotoxizität, Sterilität bei Cytosta­tika und ionisierenden Strahlen, Hirnödem bei Tranexam­säure, Anti-Antikörperbildung mit Gefahr einer Serumkrankheit bei Behandlung mit Antikörpern.Known measures that are suitable for suppressing the immune system include treatment with antibodies against lymphoid tissue, ionizing radiation and chemical substances. Such aggressive treatment is accompanied by pronounced side effects: organotoxicity, sterility with cytostatics and ionizing radiation, brain edema with tranexamic acid, anti-antibody formation with the risk of Rays and chemical substances. Such aggressive treatment is accompanied by pronounced side effects: organotoxicity, sterility in the case of cytostatics and ionizing radiation, brain edema in the case of tranexamic acid, anti-antibody formation with the risk of serum sickness when treated with antibodies.

Eine Verwendung von humanem, physiologischen F XIII hat dagegen keine der Nebenwirkungen und wirkt bereits in niedrigen Dosen wesentlich effektiver. Selbst hohe Konzentrationen von F XIII im menschlichen Plasma schei­nen keine nachteiligen Wirkungen auszulösen, so daß sich eine hohe therapeutische Breite dieses Proteins (min­destens bis zu dem 10 fachen der normalen Plasmakonzen­tration) ergibt.
Eine wirksame Menge an Transglutaminasen zum Inhibieren des Schadens bei gefährdetem Gewebe während der Reperfu­sion, bei entzündlichen Geschehen, Subarachnoidalblutun­gen, Autoimmunerkrankungen, degenerativen Erkrankungen, Arteriosklerose, neoplastischen Erkrankungen (wie Leu­kamien, Histiocytosis X und anderen), hyperergisch-al­lergischen Erkrankungen, Verbrennungskrankheit, Trans­plantatunverträglichkeit, vorzeitiger Plazentalösung und Präeklampsie, Schocksyndrom hängt von einer Reihe von Faktoren ab, beispielsweise dem Alter und dem Gewicht des Patienten und dem klinischen Zustand.In contrast, the use of human, physiological F XIII has none of the side effects and is much more effective even in low doses. Even high concentrations of F XIII in human plasma do not appear to trigger any adverse effects, so that the therapeutic range of this protein is high (at least up to 10 times the normal plasma concentration).
An effective amount of transglutaminases to inhibit damage to tissue at risk during reperfusion, inflammatory events, subarachnoid hemorrhage, autoimmune diseases, degenerative diseases, arteriosclerosis, neoplastic diseases (such as leukemia, histiocytosis X and others), hyperergic allergic diseases, intolerance to burns, transplant intolerance, transplant disease premature detachment and pre-eclampsia, shock syndrome depends on a number of factors, such as the age and weight of the patient and the clinical condition.

Eine wirksame Dosis an einer Transglutaminase, vorzugswei­se F XIII beträgt etwa 0,7 - 3000 besonders bevorzugt 7 - 300 E*/kg/24 Stunden, applizierbar i. v. oder lösungsver­mittelt i. m.. Transglutaminasen wie F XIII können durch Zusatz von Stabilisatoren wie Albumin, Polygelin oder einer Aminosäure wie Glycin stabilisiert werden (* 1 E entspricht der Menge an F XIII in 1 ml menschlichem Citratplasma).An effective dose of a transglutaminase, preferably F XIII, is approximately 0.7-3000, particularly preferably 7-300 U * / kg / 24 hours, can be administered iv or in solution-mediated. Transglutaminases such as F XIII can be stabilized by adding stabilizers such as albumin, polygelin or an amino acid such as glycine ( * 1 E corresponds to the amount of F XIII in 1 ml of human citrated plasma).

Transglutaminasen wie F XIII können auch topisch verab­ reicht werden zur lokalen Therapie und Prophylaxe von Wundheilungsstörungen, Transplantatabstoßungen, asthmo­iden Bronchialerkrankungen, Verbrennungen und anderen mit erhöhter Makrophagenaktivität einhergehenden Erkrankun­gen.Transglutaminases such as F XIII can also be administered topically enough for local therapy and prophylaxis of wound healing disorders, graft rejection, asthmoid bronchial diseases, burns and other diseases associated with increased macrophage activity.

Medizinisch indiziert sind Kombinationen aus Transgluta­minasen und einem Fibrinolytikum wie Gewebe-Plasminogen­aktivator (t-PA), Urokinase, Streptokinase oder Plasmino­gen-Streptokinase-Aktivatorkomplex zur Lysetherapie vorzugsweise bei arteriellen Verschlüssen wie bei Myokardinfarkt oder Apoplex. Ein kombinierter Einsatz von Transglutaminasen und Fibrinolytikum ermöglicht die sofortige Inhibition von Gewebeschäden (z. B. Nekrosen) während und nach akuter Reperfusion bedingt durch hyper­aktive weiße Blutzellen.Combinations of transglutaminases and a fibrinolytic such as tissue plasminogen activator (t-PA), urokinase, streptokinase or plasminogen streptokinase activator complex for lysis therapy are medically indicated, preferably for arterial occlusions such as myocardial infarction or apoplex. A combined use of transglutaminases and fibrinolytic enables the immediate inhibition of tissue damage (e.g. necrosis) during and after acute reperfusion due to hyperactive white blood cells.

Desweiteren indiziert sind Kombinationen aus Transgluta­minasen mit Antithrombin III, humanen plasmatischen oder gentechnologischen Ursprungs zur Verwendung als Immun­suppressivum.Combinations of transglutaminases with antithrombin III, human plasma or genetic engineering origin are also indicated for use as an immunosuppressant.

Medizinisch in bevorzugter Weise angezeigt sind Kombina­tionen aus Transglutaminasen mit Plasminogen-Aktivator-­Inhibitor plazentaren Ursprungs (PAI-2) zur Verwendung als Immunsuppressivum. Wird PAI-2 in einer Kombination mit Transglutaminasen verwendet, dann beträgt eine wirksame Dosis an PAI-2 bis 30 000 im allgemeinen 0.7 - 3 000 Urokinase-inhibierende Einheiten/kg/24 Stunden, d.h. 52,5 - 225 000 Einheiten für einen 75 kg schweren Patienten für die systemische Applikation.Combinations of transglutaminases with a plasminogen activator inhibitor of placental origin (PAI-2) for use as an immunosuppressant are medically preferred. When PAI-2 is used in combination with transglutaminases, an effective dose of PAI-2 is generally from 30 to 30,000 urokinase-inhibiting units / kg / 24 hours, i.e. 52.5 - 225,000 units for a 75 kg patient for systemic application.

Im folgenden wird die Wirkung von Transglutaminasen auf die Immunantwort der Maus und des Menschen in ausgewähl­ten in vivo- und in vitro-Standardtestmethoden, die bekanntermaßen für die Beurteilung von Immunsuppressoren herangezogen werden, beispielhaft erläutert. durchgeführt. Eine Kontrolle mit gereinigtem plasma­tischen F XIII führte zu vergleichbaren Ergebnissen.In the following, the effect of transglutaminases on the immune response of the mouse and of humans in selected in vivo and in vitro standard test methods, which are known to be used for the assessment of immunosuppressors, is exemplified. carried out. A control with purified plasmatic F XIII led to comparable results.

Beispiel 1example 1 Einfluß von Faktor XIII auf die Stimulation humaner Phagozyten in vitro - additiver Effekt von F XIII plus Plasminogen-Aktivator-Inhibitor-2Influence of factor XIII on stimulation of human phagocytes in vitro - additive effect of F XIII plus plasminogen activator inhibitor-2

Es wurden polymorphkernige Granulozyten und mononukleäre Phagozyten aus peripherem Blut gesunder Spender gewonnen und nach Gabe des Präparates auf verschiedene Funktionen geprüft. Als Parameter der Phagozytenfunktion wurden die Chemilumineszenzreaktion und die Sekretion lysosomaler Enzyme untersucht. Gemessen wurde sowohl die Wirkung von Faktor XIII auf die nicht-aktivierten (-IC) als auch auf die durch die durch Immunkomplexe aktivierten Phagozyten (+IC).Polymorphonuclear granulocytes and mononuclear phagocytes were obtained from peripheral blood of healthy donors and tested for various functions after administration of the preparation. The chemiluminescence reaction and the secretion of lysosomal enzymes were investigated as parameters of the phagocyte function. Both the effect of factor XIII on the non-activated (-IC) and on the phagocytes (+ IC) activated by immune complexes was measured.

Verglichen mit Phagozyten der entsprechenden Kontroll­gruppen (unbehandelte Zellen) war die Chemilumineszenzre­aktion (Generierung von Sauerstoff-Radikalen) sowohl bei humanen Granulozyten als auch Monozyten (Phagozyten) dosisabhängig signifikant erniedrigt (Tabelle 1).Compared to phagocytes from the corresponding control groups (untreated cells), the chemiluminescence reaction (generation of oxygen radicals) was significantly reduced in both granulocytes and monocytes (phagocytes) (Table 1).

Diese supprimierende Wirkung von Faktor XIII ist noch deutlicher bei einer Co-Stimulation in vitro mit Immun­komplexen IC (50 µg/ml) ausgeprägt. Humane mononukleäre Phagozyten, die mit der Substanz behandelt werden, zeichnen sich auch besonders dadurch aus, daß bei Ihnen die Sekretion lysosomaler Enzyme deutlich inhibiert ist (Tabelle 2).
Werden 0.05 E F XIII in Kombination mit 0.1 E plazentaren Plasminogen-Aktivator-Inhibitor (PAI-2) unter IC-Stimula­tion gegeben, ergibt sich eine Inhibition auf unter 40% trotz einer Inhibition von ca. 50% der Einzelsubstanzen, was eine synergistische Wirkungsweise beider Substanzen erklärt.This suppressive effect of factor XIII is even more pronounced when co-stimulated in vitro with immune complex IC (50 µg / ml). Human mononuclear phagocytes that are treated with the substance are also particularly characterized by the fact that the secretion of lysosomal enzymes is significantly inhibited (Table 2).
If 0.05 EF XIII in combination with 0.1 E placental plasminogen activator inhibitor (PAI-2) is given with IC stimulation, the result is an inhibition to below 40% despite an inhibition of approx. 50% of the individual substances, which explains the synergistic mode of action of both substances.

Beispiel 2Example 2 Wirkung von Faktor XIII auf die Aktivität von Maus-Peri­tonealmakrophagen in vivoEffect of factor XIII on mouse peritoneal macrophage activity in vivo

Weiblichen NMRI Mäuse (18 - 20 g) wurde Faktor XIII in Konzentrationen von 0,25 - 2,5 E/Tier parenteral verab­reicht. Die Kontrollen erhielten gleiche Volumina (0,5 ml) des Lösungsmittels (physiologisch gepufferte Koch­salzlösung, pH 7,2). Zwei Stunden und 24 Stunden später wurden die Mäuse getötet, ihnen die Makrophagen aus der Bauchhöhle entnommen und eine Aktivitätsbestimmung mit Hilfe der Chemilumineszenz, wie im Beispiel 1 beschrieben, durchgeführt. Wie aus Tabelle 3 ersichtlich ist, ernie­drigt Faktor XIII die Aktivität von Makrophagen, die Mäusen entnommen wurden, welche zuvor mit dem Präparat behandelt wurden. Die Suppression wurde bei der Chemi­lumineszenz sowohl nach 2 Stunden als auch nach 24 Stunden nach Applikation der Substanz mit und ohne Zusatz von Immunkomplexen in vitro beobachtet.Female NMRI mice (18-20 g) were administered factor XIII in concentrations of 0.25-2.5 U / animal parenterally. The controls received equal volumes (0.5 ml) of the solvent (physiologically buffered saline, pH 7.2). Two hours and 24 hours later, the mice were sacrificed, the macrophages were taken from the abdominal cavity, and an activity was determined using chemiluminescence, as described in Example 1. As can be seen from Table 3, factor XIII lowers the activity of macrophages taken from mice previously treated with the preparation. The suppression was observed in chemiluminescence both after 2 hours and after 24 hours after application of the substance with and without the addition of immune complexes in vitro.

Beispiel 3Example 3 Einfluß von F XIII auf die Überlebenszeit von transplan­tierter RattenschwanzhautInfluence of F XIII on the survival time of transplanted rat tail skin

In diesem Experimentalansatz wurden Schwanzhautstückchen von Lewis-Ratten mit einer Größe von etwa 0,5 x 1,0 cm auf den Schwanz von Fischer-Ratten verpflanzt. Die transplantierten Hautstücke werden vom Immunsystem der Empfängertiere als fremd erkannt und abgestoßen. Wie in der Tabelle 4 zu sehen ist, betrug die Transplantatüber­lebenszeit im Lewis-Fischer-Rattenmodell in den Kontroll­gruppen, die nur mit dem Lösungsmittel behandelt wurden, zwischen 16 und 18 Tagen. Faktor XIII (5 E/Tier) wurden intraperitoneal an 7 aufeinanderfolgenden Tagen entweder beginnend am Tag 1 oder am Tag 10 nach der Transplanta­tion verabreicht. Hierbei zeigte sich überraschend, daß Faktor XIII in der benutzten Konzentration die Überle­benszeiten der Transplantate von 17,0 ± 1,4 auf 24,8 ± 1,9 bzw. 26,8 ± 2,2 erhöhte. Tabelle 1 Einfluß von Faktor XIII auf den oxydativen Stoffwechsel (Chemilumineszenz) mit und ohne Immunkomplexstimulation (50 µg/ml) in vitro Chemilumineszenz Zelltyp Faktor XIII (E/ml) Integral der RLU/15 min.(x10³) -IC +IC Human-Monozyten (Phagozyten) 1x10⁶ Zellen 0 1674 ± 245 19775 ± 1450 2.5 252 ± 48 947 ± 152 1.2 384 ± 95 1294 ± 58 0.6 474 ± 61 2195 ± 35 0.3 575 ± 61 5195 ± 488 0.03 637 ± 81 6850 ± 354 0.01 873 + 75 10055 + 629 Human-Granulozyten 2x10⁵ Zellen 0 2678 ± 353 58650 ± 2124 2.5 148 ± 24 6448 ± 1505 1.2 342 ± 31 9583 ± 1193 0.6 645 ± 68 15733 ± 2035 0.3 863 ± 51 18700 ± 1114 0.03 1075 ± 134 26900 ± 1556 0.01 1226 ± 186 37400 ± 2851 RLU = Relative Lichteinheiten Tabelle 2 Einfluß von Faktor XIII auf die Makrophagenaktivität (Human-Monozyten, 3 x 10⁶ Zellen) in vitro. Faktor XIII (Einheiten/ml) Enzymfreisetzung (N-Ac-Glu, mU/ml) - IC + IC 0 8365 ± 219 16205 ± 1703 2.5 2514 ± 574 2723 ± 333 0.6 4254 ± 541 6428 ± 1112 0.3 6358 ± 632 10320 ± 1030 0.03 7703 ± 288 13483 ± 794 Tabelle 3 Einfluß von Faktor XIII auf die Makrophagenaktivität (1 x 10⁶ Zellen) in vivo. Faktor XIII E/Tier 1 x i.p. Chemilumineszenz Integral der RLU/15 Min. (x 10³) - IC + IC 2 Std. 24 Std. 2 Std. 24 Std. 2.5 268 ± 54 496 ± 79 - 4463 ± 567 1.0 512 ± 103 959 ± 163 - 8485 ± 707 0.5 981 ± 111 1290 ± 240 - 11300 ± 1424 0.25 1113 ± 67 2105 ± 276 - 16233 ± 2706 0 2775 ± 375 4480 ± 453 - 36767 ± 3227 Tabelle 4 Effekt von Faktor XIII auf die Hauttransplantation bei Fischer-Ratten Substanz Tage der Transplantatabstoßung Mittelwert (Tage) (x ± s) Kontrolle 19, 18, 16, 16, 16 17,0 ± 1,4 Faktor XIII 5 E/Tier, 7 x i.p. day 1-7 22, 27, 24, 26, 25 24,8 ± 1,9 Faktor XIII 5 E/Tier, 7 x i.p. day 10-17 30, 27, 24, 27, 26 26,8 ± 2,2 In this experimental approach, tail skin pieces from Lewis rats with a size of approximately 0.5 × 1.0 cm were transplanted onto the tail of Fischer rats. The transplanted skin pieces are recognized as foreign by the immune system of the recipient animals and rejected. As in As seen in Table 4, the graft survival in the Lewis Fischer rat model was between 16 and 18 days in the control groups treated with the solvent only. Factor XIII (5 U / animal) was administered intraperitoneally on 7 consecutive days, either starting on day 1 or on day 10 after the transplant. It was surprisingly found that factor XIII increased the survival times of the grafts from 17.0 ± 1.4 to 24.8 ± 1.9 and 26.8 ± 2.2 in the concentration used. Table 1 Influence of factor XIII on the oxidative metabolism (chemiluminescence) with and without immune complex stimulation (50 µg / ml) in vitro Chemiluminescence Cell type Factor XIII (U / ml) Integral of the RLU / 15 min. (X10³) -IC + IC Human monocytes (phagocytes) 1x10⁶ cells 0 1674 ± 245 19775 ± 1450 2.5 252 ± 48 947 ± 152 1.2 384 ± 95 1294 ± 58 0.6 474 ± 61 2195 ± 35 0.3 575 ± 61 5195 ± 488 0.03 637 ± 81 6850 ± 354 0.01 873 + 75 10055 + 629 Human granulocytes 2x10⁵ cells 0 2678 ± 353 58650 ± 2124 2.5 148 ± 24 6448 ± 1505 1.2 342 ± 31 9583 ± 1193 0.6 645 ± 68 15733 ± 2035 0.3 863 ± 51 18700 ± 1114 0.03 1075 ± 134 26900 ± 1556 0.01 1226 ± 186 37400 ± 2851 RLU = Relative light units Influence of factor XIII on macrophage activity (human monocytes, 3 x 10⁶ cells) in vitro. Factor XIII (units / ml) Enzyme release (N-Ac-Glu, mU / ml) - IC + IC 0 8365 ± 219 16205 ± 1703 2.5 2514 ± 574 2723 ± 333 0.6 4254 ± 541 6428 ± 1112 0.3 6358 ± 632 10320 ± 1030 0.03 7703 ± 288 13483 ± 794 Influence of factor XIII on macrophage activity (1 x 10⁶ cells) in vivo. Factor XIII E / Tier 1 x ip Chemiluminescence Integral of the RLU / 15 min. (X 10³) - IC + IC 2 hours. 24 hours 2 hours. 24 hours 2.5 268 ± 54 496 ± 79 - 4463 ± 567 1.0 512 ± 103 959 ± 163 - 8485 ± 707 0.5 981 ± 111 1290 ± 240 - 11300 ± 1424 0.25 1113 ± 67 2105 ± 276 - 16233 ± 2706 0 2775 ± 375 4480 ± 453 - 36767 ± 3227 Effect of factor XIII on skin grafting in Fischer rats substance Transplant rejection days Mean (days) (x ± s) control 19, 18, 16, 16, 16 17.0 ± 1.4 Factor XIII 5 E / animal, 7 x ip days 1-7 22, 27, 24, 26, 25 24.8 ± 1.9 Factor XIII 5 E / animal, 7 x ip day 10-17 30, 27, 24, 27, 26 26.8 ± 2.2

Claims (11)

1. Verfahren zur Herstellung eines Arzneimittels zur Immunsuppression, dadurch gekennzeichnet, daß eine Transglutaminase und gegebenenfalls ein Plasminogen-­Aktivator-Inhibitor gegebenenfalls unter Zusatz eines Hilfsstoffs oder Stabilisators in eine zur Darreichung geeignete Form bringt.1. A process for the preparation of a medicament for immunosuppression, characterized in that a transglutaminase and optionally a plasminogen activator inhibitor, optionally with the addition of an auxiliary or stabilizer, is brought into a form suitable for administration. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß als Transglutaminase Faktor XIII verwendet wird.2. The method according to claim 1, characterized in that factor XIII is used as transglutaminase. 3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein Arzneimittel für die Therapie und Prophylaxe von Transplantatabstoßungskrisen und Plazentatrophoblast­störungen und Graft versus Host-Reaktionen hergestellt wird.3. The method according to claim 1, characterized in that a medicament for the therapy and prophylaxis of graft rejection crises and placental atrophoblast disorders and graft versus host reactions is produced. 4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein Arzneimittel für die Therapie von Autoimmunerkran­kungen hergestellt wird.4. The method according to claim 1, characterized in that a medicament for the therapy of autoimmune diseases is produced. 5. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein Arzneimittel für die Therapie von Krankheitsprozes­sen, die mit erhöhter Sauerstoff-Radikalbildung einhergehen, hergestellt wird.5. The method according to claim 1, characterized in that a medicament for the therapy of disease processes associated with increased oxygen radical formation is produced. 6. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein Mittel für die Therapie und Prophylaxe von Gewebe­schäden während und nach akuter Reperfusion herge­stellt wird.6. The method according to claim 1, characterized in that an agent for the therapy and prophylaxis of tissue damage is produced during and after acute reperfusion. 7. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein Mittel zur topischen Anwendung hergestellt wird.7. The method according to claim 1, characterized in that an agent for topical application is prepared. 8. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein Mittel für die Unterdrückung des Monocyten-Makro­phagen-Systems hergestellt wird.8. The method according to claim 1, characterized in that an agent for the suppression of the monocyte-macrophage system is prepared. 9. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß 52,5 bis 225 000 Einheiten pro Dosis (75 kg Körpergewicht) Transglutaminase verwendet werden.9. The method according to claim 1, characterized in that 52.5 to 225,000 units per dose (75 kg body weight) transglutaminase are used. 10. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein Plasminogen-Aktivator-Inhibitor, vorzugsweise PAI-2, zugesetzt wird.10. The method according to claim 1, characterized in that a plasminogen activator inhibitor, preferably PAI-2, is added. 11. Verfahren nach Anspruch 10, dadurch gekennzeichnet, daß 52,5 bis 225 000 Einheiten pro Dosis (75 kg Körpergewicht) Transglutaminase und 525 - 225 000 Einheiten Plasminogen-Aktivator-Inhibitor pro Dosis enthält.11. The method according to claim 10, characterized in that 52.5 to 225,000 units per dose (75 kg body weight) contains transglutaminase and 525 - 225,000 units of plasminogen activator inhibitor per dose.
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